Gene ORGANizer: linking genes to the organs they affect

Abstract One of the biggest challenges in studying how genes work is understanding their effect on the physiology and anatomy of the body. Existing tools try to address this using indirect features, such as expression levels and biochemical pathways. Here, we present Gene ORGANizer (geneorganizer.huji.ac.il), a phenotype-based tool that directly links human genes to the body parts they affect. It is built upon an exhaustive curated database that links >7000 genes to ∼150 anatomical parts using >150 000 gene-organ associations. The tool offers user-friendly platforms to analyze the anatomical effects of individual genes, and identify trends within groups of genes. We demonstrate how Gene ORGANizer can be used to make new discoveries, showing that chromosome X is enriched with genes affecting facial features, that positive selection targets genes with more constrained phenotypic effects, and more. We expect Gene ORGANizer to be useful in a variety of evolutionary, medical and molecular studies aimed at understanding the phenotypic effects of genes.

[1]  August E. Woerner,et al.  Gibbon genome and the fast karyotype evolution of small apes , 2014 .

[2]  Luis Serrano,et al.  Correlation of mRNA and protein in complex biological samples , 2009, FEBS letters.

[3]  C. Janeway.  Immunobiology: The Immune System in Health and Disease , 1996 .

[4]  Léon Personnaz,et al.  Enrichment or depletion of a GO category within a class of genes: which test? , 2007, Bioinform..

[5]  Peter N. Robinson,et al.  Human genotype–phenotype databases: aims, challenges and opportunities , 2015, Nature Reviews Genetics.

[6]  William Davies,et al.  Genomic imprinting effects on brain development and function , 2007, Nature Reviews Neuroscience.

[7]  W. Vogel,et al.  A high density of X-linked genes for general cognitive ability: a run-away process shaping human evolution? , 2001, Trends in genetics : TIG.

[8]  Hans-Dieter Pohlenz,et al.  PhenomicDB: a multi-species genotype/phenotype database for comparative phenomics , 2005, Bioinform..

[9]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[10]  Cathy H. Wu,et al.  UniProt: the Universal Protein knowledgebase , 2004, Nucleic Acids Res..

[11]  David L. Steffen,et al.  The DNA sequence of the human X chromosome , 2005, Nature.

[12]  E. Marcotte,et al.  Insights into the regulation of protein abundance from proteomic and transcriptomic analyses , 2012, Nature Reviews Genetics.

[13]  S. S. Weinreich,et al.  Orphanet : een Europese database over zeldzame ziekten , 2008 .

[14]  Araxi O. Urrutia,et al.  Evidence that the human X chromosome is enriched for male-specific but not female-specific genes. , 2003, Molecular biology and evolution.

[15]  W. Rice.  SEX CHROMOSOMES AND THE EVOLUTION OF SEXUAL DIMORPHISM , 1984, Evolution; international journal of organic evolution.

[16]  Antonio Rosas,et al.  Thin-plate spline analysis of allometry and sexual dimorphism in the human craniofacial complex. , 2002, American journal of physical anthropology.

[17]  Peggy Hall,et al.  The NHGRI GWAS Catalog, a curated resource of SNP-trait associations , 2013, Nucleic Acids Res..

[18]  Deanna M. Church,et al.  ClinVar: public archive of relationships among sequence variation and human phenotype , 2013, Nucleic Acids Res..

[19]  H. Spencer,et al.  A census of mammalian imprinting. , 2005, Trends in genetics : TIG.

[20]  W. Rice,et al.  The X chromosome is a hot spot for sexually antagonistic fitness variation , 2002, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[21]  H. Chandra,et al.  An apparent excess of sex– and reproduction–related genes on the human X chromosome , 1999, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[22]  Jaime Prilusky,et al.  GeneCards: a novel functional genomics compendium with automated data mining and query reformulation support , 1998, Bioinform..

[23]  Melinda R. Dwinell,et al.  The Rat Genome Database 2013—data, tools and users , 2013, Briefings Bioinform..

[24]  Nuno A. Fonseca,et al.  Expression Atlas update—a database of gene and transcript expression from microarray- and sequencing-based functional genomics experiments , 2013, Nucleic Acids Res..

[25]  Minoru Kanehisa,et al.  KEGG as a reference resource for gene and protein annotation , 2015, Nucleic Acids Res..

[26]  M. Cornel,et al.  [Orphanet: a European database for rare diseases]. , 2008, Nederlands tijdschrift voor geneeskunde.

[27]  Christian Stolte,et al.  Comprehensive comparison of large-scale tissue expression datasets , 2015, bioRxiv.

[28]  P. Provero,et al.  Genome-wide signatures of convergent evolution in echolocating mammals , 2013, Nature.

[29]  C. Hutchison,et al.  The DNA sequence of the human cytomegalovirus genome. , 1991, DNA sequence : the journal of DNA sequencing and mapping.

[30]  Monica Campillos,et al.  Organ system heterogeneity DB: a database for the visualization of phenotypes at the organ system level , 2014, Nucleic Acids Res..

[31]  Irene Papatheodorou,et al.  Linking gene expression to phenotypes via pathway information , 2015, Journal of Biomedical Semantics.

[32]  Ricardo Villamarín-Salomón,et al.  ClinVar: public archive of interpretations of clinically relevant variants , 2015, Nucleic Acids Res..

[33]  H. Kraemer,et al.  Statistical issues in assessing comorbidity. , 1995, Statistics in medicine.

[34]  Caroline F. Wright,et al.  DECIPHER: database for the interpretation of phenotype-linked plausibly pathogenic sequence and copy-number variation , 2013, Nucleic Acids Res..

[35]  E. Marcotte,et al.  Global signatures of protein and mRNA expression levelsw , 2009 .

[36]  R. Feil,et al.  Regulatory links between imprinted genes: evolutionary predictions and consequences , 2016, Proceedings of the Royal Society B: Biological Sciences.

[37]  Lon Phan,et al.  Phenotype–Genotype Integrator (PheGenI): synthesizing genome-wide association study (GWAS) data with existing genomic resources , 2013, European Journal of Human Genetics.

[38]  Ashok Samal,et al.  Analysis of sexual dimorphism in human face , 2007, J. Vis. Commun. Image Represent..

[39]  M. Farhadi,et al.  A mutation in HOXA2 is responsible for autosomal-recessive microtia in an Iranian family. , 2008, American journal of human genetics.

[40]  Alan F. Scott,et al.  Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders , 2002, Nucleic Acids Res..

[41]  K. Reinhold.  Sex linkage among genes controlling sexually selected traits , 1998, Behavioral Ecology and Sociobiology.

[42]  Hana Kim,et al.  Sexual differences of imprinted genes' expression levels. , 2014, Gene.

[43]  Judith A. Blake,et al.  The Mouse Genome Database: integration of and access to knowledge about the laboratory mouse , 2013, Nucleic Acids Res..

[44]  Peter Bühlmann,et al.  Analyzing gene expression data in terms of gene sets: methodological issues , 2007, Bioinform..

[45]  Brad T. Sherman,et al.  Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists , 2008, Nucleic acids research.

[46]  E. Levanon,et al.  Human housekeeping genes, revisited. , 2013, Trends in genetics : TIG.

[47]  Núria Queralt-Rosinach,et al.  DisGeNET: a discovery platform for the dynamical exploration of human diseases and their genes , 2015, Database J. Biol. Databases Curation.

[48]  G. Rhodes.  The evolutionary psychology of facial beauty. , 2006, Annual review of psychology.

[49]  M. Lercher,et al.  Human functional genetic studies are biased against the medically most relevant primate-specific genes , 2010, BMC Evolutionary Biology.

[50]  A. Andrés,et al.  Natural Selection in the Great Apes , 2016, Molecular biology and evolution.

[51]  Damian Smedley,et al.  The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data , 2014, Nucleic Acids Res..

[52]  Thomas C. Wiegers,et al.  The Comparative Toxicogenomics Database: update 2013 , 2012, Nucleic Acids Res..

[53]  Jonathan K. Pritchard,et al.  Primate Transcript and Protein Expression Levels Evolve Under Compensatory Selection Pressures , 2013, Science.

[54]  D. Dudley,et al.  The immune system in health and disease. , 1992, Bailliere's clinical obstetrics and gynaecology.

[55]  S. Pacini,et al.  Commentary: Structural and functional features of central nervous system lymphatic vessels , 2015, Front. Neurosci..